Anal fissure is an ulcer in the squamous epithelium of the anus just distal to the mucocutaneous junction and usually in the posterior midline. It typically causes pain during defecation and for one to two hours afterwards. Even if anal fissures are rather common, pathogenesis and etiology are still incompletely understood. Nevertheless, there is evidence in the literature that anal fissures are connected with high resting anal pressure. A mucosal ischemia, in 90% of the cases in the posterior midline, may be produced if the high pressure in the anal canal exceeds the capillary pressure. Permanent elevated resting pressure is thought to impair the intrasphincteric blood flow. This reduction in mucosal blood flow leads to microcirculatory disturbance and poor healing tendency.
The fissures can be separated into acute and chronic anal fissures. A fissure has been defined as acute if it has been present for less than six weeks and chronic if it has been present for more than six weeks. Furthermore, anal fissures are claimed to affect men and women equally. Spontaneous healing occurs in 50% of the acute anal fissures in adults with or without treatment. High fibre diet is recommended and pain relief (topical anaesthetics) is reported to be effective on acute anal fissures in some people. However, a significant number of patients develop chronic anal fissures.
Surgical intervention via lateral sphincterotomy is still described as gold standard for curing chronic anal fissures. The healing rate is reported to be 94-100%. However, since sphincterotomy is associated with asymmetry of the anal canal and irreversible sphincter damage, there is a concern about long term results and fecal incontinence. The prevalence of incontinence of feces or flatus is as high as 38% after surgery. It has also been stated that there is a risk for some degree of incontinence in up to 30% of the patients that underwent sphincterotomy. This concern has over the last years led to considerations to develop medical treatments for anal fissures that temporarily and reversibly reduce anal pressure, based on the underlying pharmacology.
Recent research has revealed the basic pharmacology of the internal anal sphincter. Cook T. A. et al. provide in “The pharmacology of the internal anal sphincter and new treatments of ano-rectal disorders”, Aliment Pharmacol Ther 2001:15:887-898, a detailed overview on this aspect, which indicates potential starting points for medical treatment. The calcium concentration is considered to be the key factor for the tonus of the anal sphincter. The extracellular calcium concentration and the flux across the cell membranes through L-type calcium channels are important, as well as the calcium release from intracellular stores. Contraction is related to mechanisms that increase the intracellular calcium ion concentration above about 10−7 mol/l and relaxation to mechanisms causing a decrease in cytosolic calcium below this concentration.
Several compound classes have been evaluated over the last years as candidates for pharmacological treatment of anal fissures. These compound classes encompass NO donors, Botulinum toxin A, muscarinic agents, β-receptor agonists, α-antagonists and calcium antagonists, the calcium antagonists, and the dihydropyridines in particular, appearing to be the most promising alternative. Dihydropyridines are vasodilatory agents and are relatively smooth muscle selective.
US 2004/0028752 provides a method and composition for the treatment of an anorectal disorder and for controlling the pain associated therewith. The method comprises administering to a subject in need of such treatment therapeutically effective amounts of a calcium channel blocker either alone or together with a nitric oxide donor. In the Examples, topical application of a diltiazem hydrochloride cream is disclosed. The cream comprises 50% w/w dimethyl sulphoxide (DMSO).
For toxicological reasons, a medicament containing DMSO is undesirable. Thus, the prior art fails to provide a useful composition for the administration of a calcium antagonist for the treatment or prophylaxis of anal disorders.